Advances in Cancer Biology Research
Over the past year, research projects funded by the Division of Cancer Biology (DCB) have led to many new discoveries and advances in basic cancer research that continue to lay the groundwork for future clinical breakthroughs and cancer prevention strategies. Below are examples of important cancer biology findings.
Cancer Cell Biology
Unexpectedly, Xu et al. discovered that estrogen receptor-alpha (ERα) is an RNA-binding protein. Further, they showed that ERα RNA binding activity is critical for breast cancer growth and drug resistance.
The M2 pyruvate kinase (PKM2), an alternative-splice isoform of the PKM gene, is upregulated in most cancers and plays a crucial role in regulation of the Warburg effect. Using preclinical models, Ma et al. found that using antisense oligonucleotide (ASO)-based PKM splice switching as a targeted therapy inhibits liver cancer growth.
Mutant succinate dehydrogenase (SDH) gastrointestinal stromal tumor is a rare cancer found in the digestive tract that usually occurs in children and adolescents/young adults. Yebra et al. developed patient-derived mutant SDH tumor models that enable studies of patient-specific tumor biology and treatment strategies.
Additional research in this area is supported by the DCB Cancer Cell Biology Branch.
Cancer Immunology, Hematology, and Etiology
Liu et al. mapped cellular and gene expression alterations during leukemia development. This resource of cellular profiles (which was validated using experimental approaches) enables the understanding of cancer evolution at single-cell resolution in preclinical models.
By combining single-cell RNA and T cell receptor (TCR) sequencing, Chandran et al. revealed the immunogenicity and therapeutic potential of a mutant PIK3CA-derived neoantigen. Further, their experimental platform could be applied to the discovery of public neoantigen-specific TCRs.
Using a CRISPR-Cas9 screening approach and experimental models, Lin et al. identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical regulator of cell death in acute myeloid leukemia.
Additional research in this area is supported by the DCB Cancer Immunology, Hematology, and Etiology Branch.
DNA and Chromosome Aberrations
Kang et al. found that BRCA2 associates with MCM10 to suppress Primase-Polymerase (PRIMPOL)-mediated DNA repair. Overall, the findings establish an important function for BRCA2, provide insights into replication fork control during the DNA damage response, and may have implications for tumor suppression and therapy response.
Chaligne et al. performed multiomics single-cell profiling of diffuse gliomas. They revealed that epigenetic changes reflect cellular states in brain tumors and may contribute to their growth.
Researchers designed a new type of drug that causes lethal DNA damage in a type of brain cancer called glioblastoma, but not in normal cells.
Recurrent loss-of-function mutations in TET proteins are frequent in diffuse large B cell lymphoma (DLBCL). Shukla et al. found that TET deficiency promotes oncogenesis that is associated with the accumulation of G-quadruplex and R-loop structures in DNA.
Additional research in this area is supported by the DCB DNA and Chromosome Aberrations Branch.
Biophysics, Bioengineering, and Computational Sciences
Zhao et al. developed slide-DNA-seq, a method for capturing spatially resolved DNA sequences from intact tissue sections. This multi-modal spatial genomics approach provides a platform for quantifying how cell-intrinsic and cell-extrinsic factors contribute to gene expression, protein abundance, and other cellular phenotypes.
Researchers found that cancer cells use straw-like nanotubes to siphon mitochondria from immune cells, essentially draining their energy.
Extrachromosomal DNA (ecDNA) elements are vehicles for oncogene amplification. Using live-cell imaging, Yi et al. revealed fundamental ecDNA properties, highlighting uneven and random segregation of ecDNA and ecDNA hubs that drive gene transcription.
The epidermal growth factor receptor (EGFR) is frequently mutated in cancer; however, EGFR inhibitors have not been successful in glioblastoma multiforme (GBM), where mutations occur exclusively in the extracellular region. Using X-ray crystallography, Hu et al. showed that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands.
Additional research in this area is supported by the DCB Biophysics, Bioengineering, and Computational Sciences Branch (BBCSB).
Tumor Biology and Microenvironment
Helms et al. identified a cancer-associated fibroblast (CAF) subpopulation from a defined cell of origin, which plays a unique role in establishing the pancreatic tumor microenvironment. Overall, the findings suggests that mesenchymal lineage heterogeneity contributes to the diversification of CAFs in pancreatic cancer.
Dormancy plays a major role in the development of metastasis and residual disease in skin cancer. Using preclinical models, Fane et al. found that age-induced changes in metastatic microenvironments promote the reactivation of dormant melanoma cells in the lung.
By combining single nuclei RNA sequencing, spatial transcriptomics, and single-cell resolution spatial proteomic analysis, Gouin et al. identified an epithelial cell subpopulation that predicts response to surgery, chemotherapy and immunotherapy in bladder cancer.
Additional research in this area is supported by the DCB Tumor Biology and Microenvironment Branch.
Using single-cell RNA sequencing, immunofluorescence, and experimental models, Gong et al. found that lung fibroblasts remodel the immune microenvironment to promote breast cancer metastasis. Additionally, they showed that targeting prostaglandin E2 signaling improves the efficacy of immunotherapy.
Metastasis is the leading cause of cancer-related deaths and often arises from disseminated tumor cells that can remain dormant for years or decades. Using experimental models and RNA sequencing, Khalil et al. showed that an agonist of NR2F1 (a nuclear receptor) suppresses head and neck squamous cell carcinoma metastasis by inducing cancer cell dormancy.
Gonzalez et al. generated and analyzed a comprehensive catalog of the functional cell types and states present in brain metastases as a resource for the broader community. During the analysis, they also identified two functional cell state patterns of brain metastases that are shaped through tumor-immune interactions.
Additional research in this area is supported by the DCB Tumor Metastasis Branch.
DCB Research Programs
Reticker-Flynn et al. with the Cancer Systems Biology Consortium (CSBC) showed that cancer cells in the lymph nodes encourage immune cells to protect tumors rather than attack them. This helps the tumor spread to the rest of the body.
Rajukar et al. with the Physical Sciences- Oncology Network (PS-ON) found that 3TC (a medication used to treat HIV infection) disrupts the oncogenic functions of repeat RNAs and tumor progression in metastatic colorectal cancer.
Fitzgerald et al. with the Oncology Models Forum developed a mouse model that enables studies of anti-tumor immunity and responses to immunotherapies in KRAS-driven lung cancer.
DCB research programs supported these studies, as well as foster emerging areas and model development in cancer biology.